Specifically, we are developing novel diffusion MRI-based modeling frameworks to enable us to see fine-scale structures in the living human brain that are three orders of magnitude smaller than the underlying voxel size and are currently invisible in clinical MRI scans. To be concrete, we acquire images with voxels that are about 1.5 mm on each side of a cube, but we plan to be able to observe features of microscopic objects, like axon diameters and axon diameter distributions that require a resolution of about 2 microns. The way we can drill down into the voxel is to mathematical/physical model the relationship between the observed MR signal and the various microstructural parameters under investigation, and then to correct for various artifacts that can blur or corrupt these images. This entails combining novel diffusion MRI pulse sequences, and methods to model the biophysical origin of these signals. One method we are trying to enable is AxCaliber, an approach we invented and developed at the NIH, but which was too demanding to be performed on conventional MRI scanners. The new Connectome 2.0 scanner should allow to see axons with finer axon diameters than conventional scanners. Another approach we are in the process of migrating is mean apparent propagator (MAP) MRI, a method that measures the net displacement distribution or average propagator of diffusing water molecules in tissue. This provides information about the different microenvironments water finds itself in within living brain tissue. We also are investigating various multiple-pulsed field gradient MRI methods, some of which we have previously developed in our lab, which we are extensively vetting, and working to migrate to this powerful new clinical scanning platform. In the coming two years, much additional vetting and testing will be required to ensure the accuracy and precision of our modeling pipelines so that they are ready for clinical implementation and testing in the out years of this grant proposal when the prototype Connectome 2.0 scanner is ready to be used. We look forward to having greater flexibility and freedom in hiring new staff for this important project in the coming fiscal years. Current hiring limitations of FTEs and contractors have hampered this effort in FY'19.